Cardiovascular disease is major cause of morbidity and mortality in type 2 diabetes (T2 DM). However, it is not well-established whether aggressively lowering glucose slows or prevents development of atherosclerosis and clinical trials implementing this strategy have not reduced cardiovascular disease (CVD) in this group of individuals. Recent studies suggest that intensive glucose lowering in T1 DM may reduce atherosclerosis and CVD events, but only many years after the period of intensive therapy. These studies in T1 DM raise the very important possibility that metabolic interventions may have long- term benefits on the vasculature, creating vascular metabolic memory that continues to protect against atherosclerosis years after the intervention is discontinued. This hypothesis, if true, has major implications for management of diabetes. However, given the pathophysiologic and metabolic differences between these two forms of diabetes and the plethora of other CVD risk factors that may modulate atherosclerosis and vascular function in T2 DM, it is imperative that the concept of vascular metabolic memory be tested in persons with T2 DM. The current study takes advantage of a unique opportunity, the ending of both the 7-year VA Diabetes Trial (VADT) of tight glycemic control and complications, and an accompanying study of subclinical atherosclerosis in a subset of VADT subjects, and the beginning of the VADT observational follow-up study to test the hypothesis of vascular metabolic memory in T2 DM. We will determine if intensive glucose lowering in T2 DM during the VADT will have favorable effects on subsequent progression of atherosclerosis (vascular metabolic memory) in multiple vascular beds and whether this can be partly explained by improvements in direct and indirect pathways of glucose-mediated injury. In 460 subjects who participated in the VADT, we will measure progression of atherosclerosis using both measures of coronary and abdominal aortic calcium and carotid intima-media thickening during a 5-year period after the completion of the VADT. We will also compare the rates of change in vascular calcium between the same individuals during and after the VADT. Using serum measures of glycemic control, renal function and novel risk factors during and after the VADT, we will also explore to what extent the benefit of glucose lowering has on vascular metabolic memory can be explained by modulating components of the advanced glycation endproduct signaling pathway, or inhibiting development and progression of renal disease. Finally, we will explore the hypothesis that the period of improved glucose control during the VADT will reduce the link between extent of atherosclerosis and future CVD events. PUBLIC HEALTH RELEVANCE: The proposed study takes advantage of a well characterized cohort within a large, multicenter study with sites located throughout the U.S., providing a diverse study group that is quite representative of individuals with T2 DM within the largest healthcare system in the nation. This provides a rare opportunity to determine the specific role of glucose in human atherogenesis, and perhaps more importantly, to determine whether intensive efforts to lower glucose may translate into reduced atherosclerosis progression over many years. This is not a trivial question, as atherosclerotic disease in T2 DM is the primary cause of morbidity and mortality, and intensive diabetes treatment carries both a substantial financial and manpower burden and a potential for more frequent and severe hypoglycemia.